Formation of new neurons takes place throughout life in two discrete areas in the adult brain: the subventricular zone and the subgranule layer of the dentate gyrus. Increasing evidence suggests that newly formed neurons integrate in specific brain areas and play a role in numerous aspects of learning and memory. Our studies in mouse models of Familial Alzheimer's disease (FAD) revealed that neurogenesis is severely compromised in these mice. Impairments in neurogenesis are apparent very early in life, preceding amyloid deposition and memory deficits. For example, in transgenic mice harboring FAD- linked mutant APPswe/PS1?E9 onset of amyloid deposition is 4-5 months of age and cognitive deficits are apparent at 8-9 months, while impairments in neurogenesis are detected at 1-2 months of age. These observations suggest that alterations in neurogenesis may provide us with an early diagnostic biomarker, if we know how to detect neural progenitor cells in live individuals. A recent study successfully detected neural stem cells in the healthy human brain and quantified them using Magnetic Resonance Spectroscopy (MRS). Encouraged by our preliminary ability to reproduce the results of these studies in healthy individuals, our goal in this study is to identify a neurogenesis-based diagnostic biomarker for the detection of Alzheimer's disease using magnetic resonance spectroscopy and epigenetic validation. We propose to perform a thorough investigation of neurogenesis in the healthy and Alzheimer's human brain. We have a strong collaborative team of experts in molecular neuroscience, neurogenesis and Alzheimer's disease research (Dr. Lazarov);Mouse and human brain imaging (Dr. Little and Dr. X. Joe Zhou);Diagnosis of Alzheimer's patients with specialty in Neurology and Geriatrics (Dr. Pedalty and Dr. James, respectively);Neuropsychological evaluation of the aging population, demented individuals and Alzheimer's patients (Dr. Neynhuis). Mouse brain imaging will be performed using a 9.4-Tesla MRI. Neurogenesis in the brains of transgenic mice harboring APPswe/PS1?E9 and in wild type littermates will be examined by proton 1H-MRS. This study will be immediately followed by a human study for the quantification of neural stem cells in individuals with mild cognitive impairments (MCI), AD patients and age-matched controls, using MRS at 3Tesla. We will place regions of interest in the neurogenic areas of MCI, AD patients and demographically-matched non-demented individuals, using 1H-MRS. At present, the University of Illinois at Chicago not only has two 3-Tesla MRI systems both of which are capable of high resolution MRS but also a large census of patients with AD. Additionally, we also have human subjects institutional review board approval for this project. To validate that these alterations are Alzheimer's disease-specific, we will examine alterations in gene expression in neurogenic areas, cerebrospinal fluid and in the plasma of transgenic mice and individuals affected with the disease. For this purpose, samples will be collected from mice following MRS study. Cerebrospinal fluid and plasma samples will be collected from all study participants, i.e., MCI, AD patients and age-matched controls undergoing MRS. We will examine alterations in microRNA in brain, Cerebrospinal fluid and plasma, and will compare MRS data and microRNA biomarkers in the same subjects to evaluate their comparative effectiveness at being able to provide for the early diagnosis or for following the progression of the disease. This study will provide critical and currently absent information concerning alterations in neurogenesis in Alzheimer's disease and the ways by which it can be used as a diagnostic biomarker for this disorder. PUBLIC HEALTH RELEVANCE: Using brain imaging and gene expression analysis in brain, cerebrospinal fluid and plasma of transgenic mice, human subjects with cognitive impairments and Alzheimer's disease patients, this project will determine early biomarkers for the diagnosis of Alzheimer's disease.